Emerging Therapeutic Targets Against Toxoplasma gondii: Update on DNA Repair Response Inhibitors and Genotoxic Drugs

Abstract

Toxoplasma gondii is the causative agent of toxoplasmosis in animals and humans. This infection is transmitted to humans through oocysts released in the feces of the felines into the environment or by ingestion of undercooked meat. This implies that toxoplasmosis is a zoonotic disease and T. gondii is a foodborne pathogen. In addition, chronic toxoplasmosis in goats and sheep is the cause of recurrent abortions with economic losses in the sector. It is also a health problem in pets such as cats and dogs. Although there are therapies against this infection in its acute stage, they are not able to permanently eliminate the parasite and sometimes they are not well tolerated. To develop better, safer drugs, we need to elucidate key aspects of the biology of T. gondii. In this review, we will discuss the importance of the homologous recombination repair (HRR) pathway in the parasite's lytic cycle and how components of these processes can be potential molecular targets for new drug development programs. In that sense, the effect of different DNA damage agents or HHR inhibitors on the growth and replication of T. gondii will be described. Multitarget drugs that were either associated with other targets or were part of general screenings are included in the list, providing a thorough revision of the drugs that can be tested in other scenarios.

Resveratrol induces H2A.X phosphorylation and H4K16 de-acetylation inToxoplasma gondii

“…RSV was associated to HRR inhibition through the inactivation of tyrosyl-tRNA synthetase, an enzyme associated to protein synthesis but also to HRR gene regulation when translocate to nucleus [26,27]. If that were the case, RSV could be used in combination with a drug that inhibits the DSB repair pathway in T. gondii, as previously suggested [6].…”

“…The presence of H4K16ac in DNA damaged by DSB is able to recruit DNA repair proteins associated to the HRR pathway [7], among them ATM kinase that initiate the DNA damage response [6].…”

“…Toxoplasma possesses the conserved DSB repair machinery although it lacks some key effector proteins to decide the repair route: homologous recombination (HRR) or non-homologous end joining (NHEJ) [5]. Also, it has been observed that most of the components of the HRR pathway are essential and that a large number of drugs that are genotoxic or that inhibit DDR affect the growth of Toxoplasma in vitro and in vivo [6].…”

“…In addition to the phosphorylation of H2A.X and other proteins involved in DDR, there are other post-translational modifications of importance, including the ubiquitination of histones and acetylation of histone or non-histone proteins [5,6]. Within acetylations, ATM kinase must be acetylated for its activation and histone H4 acetylated on its lysine in position 16 (H4K16ac) is a mark that facilitates the HRR pathway [6,7]. Resveratrol (RSV; 3,5,4'-trihydroxystilbene) is a natural polyphenolic phytoalexin produced in plants.…”

“…RSV is a multi-target drug, that among other effects can alter the activity of some histone deacetylases HDACI/II, DNA methyl-transferases (DNMT) and an activator of Sir2, a sirtuin belonging to HDACIII [6]. It has also been shown to be linked to the expression of genes associated with HRR, and enzymes which inhibits the HRR pathway [6]. Sir2 modulates the acetylation status of H4K16 [8,9].…”